Gadolinium-based contrast agents (GBCAs) are widely used in magnetic resonance imaging (MRI) to enhance soft tissue contrast, making them indispensable in paediatric radiology. While GBCAs are generally considered safe in the adult population, questions remain about their safety in children, particularly as they are still developing and may undergo multiple scans over time. Concerns primarily centre on three potential risks: adverse drug reactions (ADRs), nephrogenic systemic fibrosis (NSF) and gadolinium deposition in brain tissue. A comprehensive analysis of 42 studies involving paediatric patients has provided important insights into the frequency and severity of these risks, clarifying current evidence on the safety of GBCA use in children.
Adverse Drug Reactions Are Rare but Differ Between Agent Types
The analysis of over 112,000 contrast-enhanced MRI examinations in paediatric patients found that ADRs were uncommon. Acute physiologic reactions occurred in 0.25% of cases, while allergic-like reactions were reported in 0.13%. Delayed reactions, which manifest more than an hour after GBCA administration, were observed at an incidence of 0.04%. Most ADRs were categorised as mild or moderate, and the rate of severe reactions was extremely low. When considering the type of GBCA used, macrocyclic agents were associated with fewer acute physiologic reactions compared to linear agents, with rates of 0.16% and 0.59%, respectively. This distinction is clinically significant, given that macrocyclic agents have a more stable chemical structure that reduces the likelihood of gadolinium dissociation.
The studies varied in design, age group and GBCA injection protocols, but these factors did not appear to significantly affect ADR rates. Prospective studies and those with high methodological quality yielded results consistent with retrospective studies, adding confidence to the findings. The analysis also included sensitivity testing to account for outliers, such as one study that reported unusually high reaction rates. Excluding this outlier resulted in more consistent data across studies, reinforcing the conclusion that ADRs in children are rare and often mild. The evidence suggests that macrocyclic agents offer a more favourable safety profile for paediatric use, supporting current clinical practice that prioritises their selection.
No Incidence of NSF Observed with Regulated GBCA Use
NSF is a rare, potentially debilitating condition historically linked to GBCA exposure in patients with compromised renal function. In the paediatric cohort of 4895 patients analysed, including 250 with renal insufficiency, there were no reported cases of NSF. The GBCA agents used in most of these studies were classified as group II agents, known to carry a lower risk of NSF. Earlier cases of NSF were typically associated with group I GBCAs and occurred before regulatory changes implemented after 2007. The absence of NSF in the reviewed literature reflects the effectiveness of these measures.
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Despite the reassuring data, caution remains essential when administering GBCAs to children with renal immaturity or pre-existing kidney disease. Neonates younger than four weeks and children with chronic kidney conditions are particularly vulnerable. Although the number of patients with renal impairment in the included studies was limited, the findings support the need for individual risk-benefit assessments in such cases. The variation in how renal insufficiency was defined across studies presents an additional consideration, but it does not undermine the central observation that regulated use of modern GBCA agents in paediatric patients has not been associated with NSF in recent clinical settings.
Gadolinium Deposition Is More Pronounced with Linear Agents
Gadolinium retention in the brain, particularly in regions such as the dentate nucleus and globus pallidus, has raised concern due to its unclear long-term implications. In the subset of studies focusing on brain deposition, a linear association was observed between the number of GBCA administrations and the signal intensity (SI) ratio in the dentate nucleus to the pons. This association was stronger for linear agents than for macrocyclic ones. The regression coefficient for linear agents was 0.004, compared to 0.0004 for macrocyclic agents, indicating a greater accumulation with linear agents.
While the data suggest a difference in deposition patterns between GBCA types, the clinical relevance of this finding remains uncertain. No long-term neurodevelopmental effects have been directly linked to gadolinium deposition in children. Nevertheless, the physicochemical differences between macrocyclic and linear agents offer a plausible explanation for the disparity. Macrocyclic agents, with their rigid cage-like structure, bind gadolinium more tightly, reducing the likelihood of free gadolinium ions accumulating in brain tissue. By contrast, the more flexible structure of linear agents makes them more susceptible to dissociation and deposition.
Given that paediatric patients are more likely to receive repeated imaging over the course of their lifetime, minimising cumulative exposure is advisable. The findings support current clinical preferences for macrocyclic GBCAs, particularly in situations where repeated imaging is anticipated. While signal intensity changes serve as an indirect measure of deposition, further research is required to understand the potential biological and clinical consequences of these deposits.
Gadolinium-based contrast agents are generally safe for use in children undergoing contrast-enhanced MRI, with a low incidence of both acute and delayed adverse drug reactions. No cases of nephrogenic systemic fibrosis were reported among nearly 5000 patients, including those with impaired renal function. Gadolinium deposition in the brain appears to correlate with the number of administrations and is more pronounced with linear agents than with macrocyclic ones. The results support the continued preferential use of macrocyclic GBCAs in paediatric imaging to mitigate potential risks. Although the evidence base is strong, ongoing surveillance and additional studies are needed to assess long-term outcomes, particularly in relation to brain deposition and neurodevelopment.
Source: Radiology
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